Research ArticleNo Association between the rs1799836 Polymorphism of theMonoamine Oxidase B Gene and the Risk of Autism SpectrumDisorders in the Kazakhstani Population

Anastassiya V. Perfilyeva ,1 Kira B. Bespalova ,2 Liliya A. Skvortsova ,1 Assel Surdeanu,1

Aleksandr A. Garshin ,1 Yuliya V. Perfilyeva,3 Ozada Kh. Khamdiyeva,1

Bakhytzhan O. Bekmanov,1 and Leyla B. Djansugurova1

1Institute of General Genetics and Cytology CS MES RK, Almaty 050000, Kazakhstan2Al-Farabi KazNU, Almaty 050000, Kazakhstan3M. Aitkozhin Institute of Molecular Biology and Biochemistry, Almaty 050000, Kazakhstan

Correspondence should be addressed to Anastassiya V. Perfilyeva; nastyaper2009@mail.ru

Received 20 March 2019; Revised 29 April 2019; Accepted 12 May 2019; Published 2 June 2019

Academic Editor: Paul Ashwood

Copyright © 2019 Anastassiya V. Perfilyeva et al. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original workis properly cited.

Autism spectrum disorders (ASDs) are heterogeneous diseases that are triggered by a number of environmental and genetic factors.The aim of the current study was to investigate an association of the rs1799836 genetic variant of the neurotransmitter-related geneMAOB with ASDs. In total, 262 patients diagnosed with ASDs and their 126 healthy siblings were included in the present study. Allindividuals represented a Kazakhstani population. The distributions of the rs1799836 genotype were in accordance with the Hardy-Weinberg equilibrium among both cases and controls. No statistically significant differences were found in the allelic distributionsof this polymorphism between ASD and control subjects (A/G: for malesOR = 1 11, 95% 0.59-2.06, p = 0 75; for femalesOR = 1 14,95% 0.70-1.86, p = 0 76). However, the increased score in the overall CARS was significantly associated with the A allele ofrs1799836 MAOB for females (OR = 2 31, 95% 1.06-5.04, p = 0 03). The obtained results suggest that the rs1799836polymorphism of the MAOB gene may have little contribution to the development of ASDs but may be involved in pathwayscontributing to ASD symptom severity in females. Further large-scale investigations are required to uncover possiblerelationships between rs1799836 MAOB and ASD progression in a gender-specific manner and their possible application as atherapeutic target.

1. Introduction

Autism spectrum disorders (ASDs) are complex childhoodneuropsychiatric disorders mainly characterized by deficitsin verbal and nonverbal communication, reciprocal socialinteractions, and stereotypical behaviors. In the last fiveyears, the number of reported cases of children with autismin Kazakhstan has increased by 1.8 times. According to theofficial data provided by the Ministry of Healthcare of theRepublic of Kazakhstan for 2018, the prevalence of ASD is2.6 per 100,000 children, which is lower than the global sta-tistics. WHO estimated that worldwide, 1 in 160 children

has an ASD with an incidence rate of 6.25 per 100,000 peo-ple. We assume that the official data do not reflect the truepicture of morbidity due to the difficulties of ASD diagnos-tics in our country.

The etiology of this pathology is extremely complex, andin most cases, the underlying pathological mechanismsremain unknown. In recent years, a number of works havebeen devoted to the study of neurochemical, immunological,structural, functional, and genetic factors of the ASD etio-pathogenesis. According to the prevailing view, autisticdisorders are pathophysiological processes caused by a com-bination of various exogenous factors encountered in the

HindawiDisease MarkersVolume 2019, Article ID 2846394, 6 pageshttps://doi.org/10.1155/2019/2846394

http://orcid.org/0000-0003-2121-0042http://orcid.org/0000-0001-8031-447Xhttp://orcid.org/0000-0002-2035-2244http://orcid.org/0000-0003-3922-0783https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://doi.org/10.1155/2019/2846394

early stages of development, as well as genetic factors. Identi-fication of candidate genes associated with a genetic predis-position to ASDs is a common molecular strategy [1].

In this study, we focused on the monoamine oxidase B(MAOB) gene, which has been considered as one of the can-didate genes by a number of studies. Monoamine oxidase(MAO) is one of the most important enzymes in neurotrans-mitter metabolism. The MAOB is a member of the mono-amine oxidase family of flavoproteins, which catalyze theoxidation of primary and secondary amines, polyamines,amino acids, and methylated lysine side chains in proteins[2]. MAOB is located in the outer mitochondrial membraneand expressed mainly in platelets, lymphocytes, and the brain[3], where it preferentially oxidizes benzylamine, beta-phenylethylamine (PEA), and dopamine [2].

PEA is a biogenic trace amine, which acts as a central ner-vous system stimulant. The role of PEA is not fully clear, butits chemical similarity to d-amphetamine suggests that thismolecule facilitates catecholamine and serotonin release [4].In the brain, PEA affects the mood and emotions and is ableto increase mental focus. Abnormal concentrations of PEAmay be associated with a number of psychological disorders[5]. It was shown that PEA, which is formed from phenylal-anine, and phenylalanine itself are reduced in the urine ofASD patients [6].

Another target of the MAOB protein is dopamine,which plays an important role in the motor control andexecutive functions and in the regulation of arousal, motiva-tion, reinforcement, and reward behaviors. It has beenshown that ASDs are associated with dopaminergic dysfunc-tions [7–11]. Abnormal dopamine was demonstrated in theurine of autistic children through the measurement of thelevel of homovanillic acid as a degradation product of dopa-mine [12]. It has been shown that de novo mutations in thedopamine transporter gene lead to dopamine dysfunctionsand may confer risk of ASDs [13]. Moreover, low maternalserum dopamine B hydroxilase levels have been demon-strated to create a nonideal intrauterine environment, whichcan lead to autistic disorders in the fetus [14].

In addition, it was shown that 30–50% of ASD patientshave increased levels of blood serotonin (5-hydroxytrypta-mine (5-HT)) [15, 16], which plays a key role in the neuronalmaturation, dendritic formation, and synaptogenesis in earlydevelopmental stages. In the condition of absence of MAOA,which is more affined for serotonin, the overlapping sub-strate specificities of the two MAO isoenzymes allow MAOBto participate in the metabolism of serotonin [17]. Takinginto account that MAOB is the only isoenzyme expressedin platelets, it may play an important role in the regulationof plasma 5-HT levels. Moreover, male MAO A/B knockoutmice exhibited a number of autistic-like behavioral changes,such as social and communication impairments, persevera-tive and stereotypical responses, and behavioral inflexibility,which were probably caused by high 5-HT levels in earlydevelopmental stages [18].

Aside from the important enzymatic functions, anotherpossible reason to consider MAOB as a candidate gene forASD susceptibility is its location on the X chromosome(Xp11.3). It is well known that ASDs are prevalent in males

(4 males : 1 female) [1], indicating that ASD risk genes canbe found in the X/Y chromosomes.

Genetic variations in the MAOB gene can affect its func-tions, contributing to the genetic predisposition to neurode-generative diseases including ASDs. Therefore, in the currentfamily-based study, samples from 262 Kazakhstani ASDpatients and their 126 healthy brothers and sisters wereanalyzed for a single nucleotide polymorphism (SNP) inintron 13 of the MAOB gene (rs1799836), which resultsin the transitional conversion of adenine (A) to guanine(G) at the position 36 bp upstream from the start positionof exon 14 (A644G). We hypothesized that genetic variantsof this SNP can contribute to ASD development in theKazakhstani population.

2. Materials and Methods

2.1. Subjects. Buccal swabs were collected from children withASD, as well as from their healthy brothers and sisters, usingsterile cotton-tipped applicators in individual plastic packs.Collected material was transported to the Institute of GeneralGenetics and Cytology in a portable refrigerated containerwithin several hours after the collection and frozen at -80°Cfor further molecular-genetic studies.

Collection of biomaterial was conducted exclusively on avoluntary basis after signing an informed consent by at leastone of the parents. The protocol of the study was approved bythe Ethics Committee of Asfendiyarov’s Kazakh NationalMedical University (No. 57, 05.09.2017).

In addition to signing an informed consent, a detailedquestionnaire and psychological testing of the children wasconducted using the Childhood Autism Rating Scale (CARS)and the Modified Checklist for Autism in Toddlers (M-Chat-R). Autism severity was classified by CARS as mild/moderate(scores below 36) and severe (scores 37-60).

2.2. Single-Nucleotide Polymorphism (SNP) Genotyping.DNA from buccal swabs was isolated using a DNA extrac-tion kit (AmpliSens). The DNA samples were stored at-20°C and -80°C. The PCR-RFLP assay was used for thegenotyping of MAOB rs1799836 single nucleotide polymor-phism as described earlier [1].

2.3. Statistical Analysis. The Hardy-Weinberg equilibrium(HWE) test for X-linked genes was used to compare theobserved and expected genotype frequencies. As MAOB islocated on the X chromosome, we stratified the data set onsex and analyzed males and females separately. Relative riskswere estimated by odds ratios (OR) with a logistic regression95% confidence interval. For females, the genotypes wereexamined using allelic and general models of inheritance;for males, only the allelic model was examined. The dataare presented as median ± SD. Power was calculated usingthe genetic power calculator OSSE.

3. Results

3.1. General Characteristics of Patients. Starting from March2018 to February 2019, a total of 262 ASD patients and their126 healthy siblings were recruited for the current study. All

2 Disease Markers

individuals represented a Kazakhstani population. Recruit-ment was carried out in rehabilitation centers of Kazakhstan.

The clinical diagnosis of autism in our work was estab-lished by senior psychiatrists and assessed by the CARS forchildren over 3 years and the M-Chat-R for children underthree years old. CARS and M-Chat-R have been used as stan-dardized, investigator-based instruments for detection ofASDs [19, 20].

Characteristics of the ASD patients and healthy controlsare summarized in Table 1. The ethnic heterogeneity ofboth groups was Kazakh, Russian, and other ethnicities(Armenians, Kyrgyz, Tatars, Uzbeks, Uigurs, Koreans,Kurds, Pakistanis, Turks, and Chechens for the ASD group;Armenians, Koreans, Tatars, Uzbeks, Uigurs, and Chechensfor the control group). In the ASD group, 77% were malesand 23% were females. In the control group, 41% were malesand 59% were females.

Subjects were divided into infancy/early childhood,prepubertal, pubertal, adolescents, and adults. Data onthe size of each group are represented in Table 1. Themost numerous were groups under the age of 15 years(97.5% for ASD male, 98.3 for ASD female, 82.6% for con-trol male, and 74.4% for control female) for which the M-Chat-R and the CARS test were used. The adolescent/adultsubjects had a clinically confirmed, long-established diag-nosis of autism.

3.2. Analysis of the Association of the rs1799836 MAOBPolymorphism with the Risk of ASD in a KazakhstaniPopulation. The genotype distributions of the rs1799836poly-morphism were in accordance with the Hardy-Weinbergequilibrium (HWE) for both the control (p = 0 949) andASD (p = 0 605) cases. The distribution of rs1799836 MAOBalleles and genotypes is presented in Table 2.

Since the MAOB gene is located on the chromosome X,both sexes were analyzed separately. No significant differ-ences were observed in the allele frequencies between theASD and controls cases (for males, p = 0 75, and for females,p = 0 76). AA genotype distribution was nonsignificantlyhigher in ASD female patients as compared to the controls(p = 0 76).

OR analysis was performed to evaluate the effect ofrs1799836 on the severity of ASD. Autism severity was clas-sified by CARS as mild/moderate (scores below 36) andsevere (scores above 36). As shown in Table 3, female ASDcases with the A allele significantly tend to be severely autisticrather than mild or moderate (p = 0 03).

4. Discussion

Our family-based study failed to prove the hypothesis thatrs1799836 of MAOB was associated with ASDs in theKazakhstani population. The obtained results showed thatthe SNP was not significantly associated with ASD develop-ment in both males and females.

Little research has been conducted so far to study theimpact of MAOB rs1799836 on ASD pathogenesis. Earlier,similar results were obtained in a study of ethnicallyhomogenous groups of male Caucasians with autism [21].

On the contrary, MAOB G allele frequency was significantlyincreased in Egyptian autistic patients more than in controls(OR = 34 and 12.5 for male and female cases, respectively;p < 0 001) [1]. Although we cannot exclude the influenceof genetic differences between populations on the results,we could also attribute the contradictory results to thesmaller sample size in the aforementioned study (cases/con-trols, 67/42) as compared to the current study (cases/con-trols, 262/126), which may lead to lower power analysis.

Nevertheless, a number of studies have shown the associ-ation of rs1799836 of MAOB with other “brain diseases.” In ameta-analysis, Y. Liu et al. found a significant relationshipbetween the A allele of the rs1799836 polymorphism andParkinson’s disease development [22]. The G allele ofrs1799836 was identified as a risk factor for developingschizophrenia (p = 0 006) in a Spanish population [23] andin Han Chinese [24].

Interestingly, our analysis further demonstrated that theseverity of autism significantly increased for A allele femalecarriers (p = 0 03), which can be possibly explained by theenzymatic activity of this allele. It has been earlier shownthat the A allele of rs1799836 is associated with significantlylower enzyme activity in platelets as compared to the Gallele [25]. The hypothesis is further supported by the factthat monoamine oxidase activity in platelets inversely corre-lates with personality characteristics such as impulsiveness,sensation-seeking, monotony avoidance, and to some degreeaggression [26, 27]. Low platelet MAO activity has beendemonstrated in alcoholics [28]. The mean MAOB activityin suicidal patients was significantly lower than in nonsuici-dal depressed patients and healthy controls (p < 0 01) [29].MAOB-deficient mice showed increased reactivity to stress[30]. Finally, the hypothesis that activity of neurotransmittergenes contributes to ASD severity is in line with recent find-ings linking MAO isoenzyme activity to ASD symptoms.Thus, it was shown that autistic males with the low-expressing 3-repeat allele of the MAOA gene had moresevere characteristics of sensory behaviors, arousal regulationproblems, aggression, and weaker social communicationskills than males with the high activity allele [31].

In summary, the obtained results indicate that rs1799836may not be directly related to the occurrence of ASDs butthrough A allele may affect the symptoms of ASDs in femalepatients. However, the study has several limitations. Subdivi-sion of all individuals to male and female groups as well as tosevere and mild/moderate ASD groups led to a relativelysmall size of the samples, so the power of these subgroupresults was

Another possible limitation of this study is the family-based design, which may imply the “contamination” of con-trol samples with “suspected” genes. Earlier, Evangelou et al.reported that both unrelated case-control and family-basedstudies gave overall similar estimates on associations in 93subgroup analyses [32]. A key benefit of such family-based

association studies is the control for confounding bias dueto population stratification [33]. Sibling controls are derivedfrom exactly the same gene pool as the cases and thus repre-sent exactly matched controls, but they do pose other practi-cal and statistical difficulties. Thus, it was shown that siblingsare more likely to have the same genotype as the case than

Table 1: Characteristics of ASD patients and control subjects.

CharacteristicASD N (%) Controls N (%)

Male Female Male Female

Sample size 202 60 52 74

Ethnicity

Kazakh 137 (68) 39 (65) 33 (64) 62 (84)

Russian 45 (22) 15 (25) 10 (19) 6 (8)

Other nationality 20 (10) 6 (10) 9 (17) 6 (8)

Age (years)Median ± SD 7 20 ± 3 69 6 73 ± 2 83 9 09 ± 6 55 9 62 ± 6 84

Range 2-33 2-16 1-29 1-29

Periods of age

Infancy/early childhood (up to 7 years old) (%) 112 (55.4) 33 (55.0) 28 (53.8) 33 (44.6)

Prepubertal (7 to 11 years old) (%) 57 (28.2) 21 (35.0) 5 (9.6) 13 (17.6)

Pubertal (11 to 15 years old) (%) 28 (13.9) 5 (8.3) 10 (19.2) 9 (12.2)

Adolescence (15 to 20 years old) (%) 4 (2.0) 1 (1.7) 6 (11.5) 14 (18.9)

Adults (above 20 years old) (%) 1 (0.5) 0 3 (5.8) 5 (6.8)

CARS scoreMedian ± SD 33 43 ± 7 53 34 07 ± 7 30 15 63 ± 1 37 16 29 ± 4 13

Range 30-52.5 30-54 15-19 15-17

Table 2: Genotype and allele distributions of MAOB in ASD patients and controls.

rs1799836 MAOBASD patients Controls

OR 95% CI p valueNo. % No. %

Male

AA 133 66 33 63 1.11 0.59-2.060.75

GG 69 34 19 37 0.90 0.48-1.68

Female

A allele 70 58 84 57 1.14 0.70-1.860.76

G allele 50 42 64 43 0.88 0.54-1.43

AA 23 37 24 32 1.30 0.64-2.64

0.76AG 26 43 36 49 0.81 0.41-1.60

GG 11 20 14 19 0.96 0.40-2.31

Table 3: Relation between MAOB polymorphisms and severity of ASDs.

MAOB rs1799836Severe

Mild andmoderate OR 95% CI p value

No. % No. %

Male

A allele 48 68 72 65 1.13 0.60-1.860.70

G allele 23 32 39 35 0.88 0.47-1.45

Female

A allele 37 71 32 52 2.31 1.06-5.040.03

G allele 15 29 30 48 0.43 0.20-0.94

AA 13 50 9 29 2.44 0.82–7.29

0.12AG 11 42 14 45 0.89 0.31–2.55

GG 2 8 8 26 0.24 0.05–1.25

4 Disease Markers

unrelated controls, thereby leading to some loss of statisticalefficiency [34]. Considering this disadvantage of the family-based design, we agree that our findings are preliminaryand need to be validated in further studies with samples ofunrelated representatives of the Kazakhstani population.

5. Conclusion

To the best of our knowledge, this is the largest study on theassociation of rs1799836 of the MAOB gene with ASD risk.Even though we found no association of the rs1799836 ofthe MAOB gene with ASD susceptibility, we are reportingon the association of the MAOB rs1799836 marker withsymptom severity in females, which implies that the SNPmay be involved in pathways contributing to ASD progres-sion in a gender-specific manner. However, further investiga-tion is needed to validate these results. If they are replicatedin future studies, the findings may be used for the develop-ment of new target therapies.

The present study is a pilot study to report on an associ-ation of the candidate genes with ASDs in the Kazakhstanipopulation. The results represent an interesting platformfor further studies on the impact of polymorphisms of neuro-transmitter genes on ASDs and its characteristics.

Data Availability

The data used to support the findings of this study areavailable from the corresponding author upon request.

Conflicts of Interest

The authors declare no conflict of interest.

Acknowledgments

The authors are grateful to the parents and children partici-pating in the study, as well as the heads of the rehabilitationcenters, who, through recruitment, have made a valuablecontribution to the success of the study. They would partic-ularly like to thank Demeuova Regina, Darmenova Ainur,Seitova Adina, Kvan Olga, and Zhumashev Gamali. We alsogratefully thank Theodore Micceri, PhD, for critical readingof the manuscript. This work was supported by the grant #0118РК00503 received from the Committee of Science, Min-istry of Education and Science of the Republic of Kazakh-stan, 2017-2019.

References

[1] A. M. Salem, S. Ismail, W. A. Zarouk et al., “Genetic variantsof neurotransmitter-related genes and miRNAs in Egyptianautistic patients,” The Scientific World Journal, vol. 2013,Article ID 670621, 7 pages, 2013.

[2] H. Gaweska and P. F. Fitzpatrick, “Structures and mechanismof the monoamine oxidase family,” Biomolecular Concepts,vol. 2, no. 5, pp. 365–377, 2011.

[3] P. A. Bond and R. L. Cundall, “Properties of monoamine oxi-dase (MAO) in human blood platelets, plasma, lymphocytes

and granulocytes,” Clinica Chimica Acta, vol. 80, no. 2,pp. 317–326, 1977.

[4] M. Bortolato, G. Floris, and J. C. Shih, “From aggression toautism: new perspectives on the behavioral sequelae of mono-amine oxidase deficiency,” Journal of Neural Transmission,vol. 125, no. 11, pp. 1589–1599, 2018.

[5] M. Irsfeld, M. Spadafore, and B. M. Prüß, “β-Phenylethyl-amine, a small molecule with a large impact,”WebmedCentral,vol. 4, no. 9, p. 4409, 2013.

[6] A. Kusaga, “Decreased beta-phenylethylamine in urine of chil-dren with attention deficit hyperactivity disorder and autisticdisorder,” No to Hattatsu, vol. 34, no. 3, pp. 243–248, 2002.

[7] T. Kriete and D. C. Noelle, “Dopamine and the development ofexecutive dysfunction in autism spectrum disorders,” PLoSOne, vol. 10, no. 3, article e0121605, 2015.

[8] A. A. Scott-Van Zeeland, M. Dapretto, D. G. Ghahremani,R. A. Poldrack, and S. Y. Bookheimer, “Reward processing inautism,” Autism Research, vol. 3, no. 2, pp. 53–67, 2010.

[9] M. Ernst, A. J. Zametkin, J. A. Matochik, D. Pascualvaca, andR. M. Cohen, “Low medial prefrontal dopaminergic activity inautistic children,” The Lancet, vol. 350, no. 9078, p. 638, 1997.

[10] G. S. Dichter, J. N. Felder, S. R. Green, A. M. Rittenberg, N. J.Sasson, and J. W. Bodfish, “Reward circuitry function inautism spectrum disorders,” Social Cognitive and AffectiveNeuroscience, vol. 7, no. 2, pp. 160–172, 2012.

[11] D. Pavăl, “A dopamine hypothesis of autism spectrum disor-der,” Developmental Neuroscience, vol. 39, no. 5, pp. 355–360, 2017.

[12] J. Kaluzna-Czaplinska, E. Socha, and J. Rynkowski, “Determi-nation of homovanillic acid and vanillylmandelic acid in urineof autistic children by gas chromatography/mass spectrome-try,” Medical Science Monitor, vol. 16, no. 9, pp. CR445–CR450, 2010.

[13] P. J. Hamilton, N. G. Campbell, S. Sharma et al., “De novomutation in the dopamine transporter gene associates dopa-mine dysfunction with autism spectrum disorder,” Molecu-lar Psychiatry, vol. 18, no. 12, pp. 1315–1323, 2013.

[14] P. D. Robinson, C. K. Schutz, F. Macciardi, B. N. White, andJ. J. A. Holden, “Genetically determined low maternal serumdopamine β-hydroxylase levels and the etiology of autismspectrum disorders,” American Journal of Medical Genetics,vol. 100, no. 1, pp. 30–36, 2001.

[15] E. J. Mulder, G. M. Anderson, I. P. Kema et al., “Platelet sero-tonin levels in pervasive developmental disorders and mentalretardation: diagnostic group differences, within-group distri-bution, and behavioral correlates,” Journal of the AmericanAcademy of Child & Adolescent Psychiatry, vol. 43, no. 4,pp. 491–499, 2004.

[16] E. R. Ritvo, A. Yuwiler, E. Geller, E. M. Ornitz, K. Saeger, andS. Plotkin, “Increased blood serotonin and platelets in earlyinfantile autism,” Archives of General Psychiatry, vol. 23,no. 6, pp. 566–572, 1970.

[17] M. Bortolato, K. Chen, and J. C. Shih, “Monoamine oxidaseinactivation: from pathophysiology to therapeutics,” AdvancedDrug Delivery Reviews, vol. 60, no. 13-14, pp. 1527–1533, 2008.

[18] M. Bortolato, S. C. Godar, L. Alzghoul et al., “Monoamine oxi-dase A and A/B knockout mice display autistic-like features,”International Journal of Neuropsychopharmacology, vol. 16,no. 4, pp. 869–888, 2013.

[19] J. M. Kleinman, D. L. Robins, P. E. Ventola et al., “The modi-fied checklist for autism in toddlers: a follow-up study

5Disease Markers

investigating the early detection of autism spectrum disor-ders,” Journal of Autism and Developmental Disorders,vol. 38, no. 5, pp. 827–839, 2008.

[20] C. Chlebowski, J. A. Green, M. L. Barton, and D. Fein, “Usingthe childhood autism rating scale to diagnose autism spectrumdisorders,” Journal of Autism and Developmental Disorders,vol. 40, no. 7, pp. 787–799, 2010.

[21] M. Nikolac Perkovic, G. Nedic Erjavec, J. Stefulj et al., “Associ-ation between the polymorphisms of the selected genes encod-ing dopaminergic system with ADHD and autism,” PsychiatryResearch, vol. 215, no. 1, pp. 260-261, 2014.

[22] Y. Liu, Z. Wang, and B. Zhang, “The relationship betweenmonoamine oxidase B (MAOB) A644G polymorphism andParkinson disease risk: a meta-analysis,” Annals of Saudi Med-icine, vol. 34, no. 1, pp. 12–17, 2014.

[23] P. Gassó, M. Bernardo, S. Mas et al., “Association of A/G poly-morphism in intron 13 of the monoamine oxidase B gene withschizophrenia in a Spanish population,” Neuropsychobiology,vol. 58, no. 2, pp. 65–70, 2008.

[24] Y. L. Wei, C. X. Li, S. B. Li, Y. Liu, and L. Hu, “Associationstudy of monoamine oxidase A/B genes and schizophrenia inHan Chinese,” Behavioral and Brain Functions, vol. 7, no. 1,p. 42, 2011.

[25] H. Garpenstrand, J. Ekblom, K. Forslund, G. Rylander, andL. Oreland, “Platelet monoamine oxidase activity is related toMAOB intron 13 genotype,” Journal of Neural Transmission,vol. 107, no. 5, pp. 523–530, 2000.

[26] L. Oreland and J. Hallman, “Chapter 8 the correlation betweenplatelet MAO activity and personality: short review of findingsand a discussion on possible mechanisms,” Progress in BrainResearch, vol. 106, pp. 77–84, 1995.

[27] D. Schalling, M. Åsberg, G. Edman, and L. Oreland, “Markersfor vulnerability to psychopathology: temperament traits asso-ciated with platelet MAO activity,” Acta Psychiatrica Scandi-navica, vol. 76, no. 2, pp. 172–182, 1987.

[28] L. Oreland, “Monoamine oxidase in neuro-psychiatric disor-ders,” in Monoamine Oxidase: Basic and Clinical Aspects,pp. 219–247, VSP Press, Utrecht, Netherlands, 1993.

[29] J. Roggenbach, B. Müller-Oerlinghausen, L. Franke,R. Uebelhack, S. Blank, and B. Ahrens, “Peripheral serotonergicmarkers in acutely suicidal patients, 1. Comparison of serotoner-gic platelet measures between suicidal individuals, nonsuicidalpatients with major depression and healthy subjects,” Journalof Neural Transmission, vol. 114, no. 4, pp. 479–487, 2007.

[30] J. Grimsby, M. Toth, K. Chen et al., “Increased stress responseand β–phenylethylamine in MAOB–deficient mice,” NatureGenetics, vol. 17, no. 2, pp. 206–210, 1997.

[31] I. L. Cohen, X. Liu, M. E. S. Lewis et al., “Autism severity isassociated with child and maternal MAOA genotypes,” Clini-cal Genetics, vol. 79, no. 4, pp. 355–362, 2011.

[32] E. Evangelou, T. A. Trikalinos, G. Salanti, and J. P. A. Ioannidis,“Family-based versus unrelated case-control designs for geneticassociations,” PLoS Genetics, vol. 2, no. 8, article e123, 2006.

[33] A. Schnell and J. Witte, “Family-based study designs,” inMolecular Epidemiology: Applications in Cancer and OtherHuman Diseases, T. R. Rebbeck, C. B. Ambrosone, and P. G.Shields, Eds., pp. 19–28, CRC Press, 2008.

[34] D. C. Thomas and J. S. Witte, “Point: population stratification:a problem for case-control studies of candidate-gene associa-tions?,” Cancer Epidemiology, Biomarkers & Prevention,vol. 11, no. 6, pp. 505–512, 2002.

6 Disease Markers

Stem Cells International

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

Disease Markers

Hindawiwww.hindawi.com Volume 2018

BioMed Research International

OncologyJournal of

Hindawiwww.hindawi.com Volume 2013

Hindawiwww.hindawi.com Volume 2018

Oxidative Medicine and Cellular Longevity

Hindawiwww.hindawi.com Volume 2018

PPAR Research

Hindawi Publishing Corporation http://www.hindawi.com Volume 2013Hindawiwww.hindawi.com

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwww.hindawi.com Volume 2018

Journal of

ObesityJournal of

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

Computational and Mathematical Methods in Medicine

Hindawiwww.hindawi.com Volume 2018

Behavioural Neurology

OphthalmologyJournal of

Hindawiwww.hindawi.com Volume 2018

Diabetes ResearchJournal of

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

Research and TreatmentAIDS

Hindawiwww.hindawi.com Volume 2018

Gastroenterology Research and Practice

Hindawiwww.hindawi.com Volume 2018

Parkinson’s Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwww.hindawi.com

Submit your manuscripts atwww.hindawi.com

https://www.hindawi.com/journals/sci/https://www.hindawi.com/journals/mi/https://www.hindawi.com/journals/ije/https://www.hindawi.com/journals/dm/https://www.hindawi.com/journals/bmri/https://www.hindawi.com/journals/jo/https://www.hindawi.com/journals/omcl/https://www.hindawi.com/journals/ppar/https://www.hindawi.com/journals/tswj/https://www.hindawi.com/journals/jir/https://www.hindawi.com/journals/jobe/https://www.hindawi.com/journals/cmmm/https://www.hindawi.com/journals/bn/https://www.hindawi.com/journals/joph/https://www.hindawi.com/journals/jdr/https://www.hindawi.com/journals/art/https://www.hindawi.com/journals/grp/https://www.hindawi.com/journals/pd/https://www.hindawi.com/journals/ecam/https://www.hindawi.com/https://www.hindawi.com/